The Next Prozac?

Ketamine is a pediatric anesthetic, a club drug, and the most promising antidepressant in decades.

The experimental drug ketamine apperars to offer hope to people whose depression hasn't yielded to other treatments. When it works, it can lift depression in hours, instead of the weeks most other antidepressants take.

But ketamine itself isn't an ideal drug. Its relief lasts only 7 to 10 days, and it has a host of side effects. It's also used illegally as the party drug "Special K." And no one has ever been able to figure out why it works so quickly.

Now, researchers at Yale University, where the original connection between ketamine and relief of depression was made, have figured out just why ketamine works so quickly. The discovery may speed development of the first new class of drugs to treat depression in 25 years.

Giving rats a single dose of ketamine restored the neural deficits caused by the exposure to stress. The restoration was nearly immediate and clearly visible under the microscope.

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Ketamine works by rapidly re-establishing connections between nerves in areas of the brain known to affect mood, including the prefrontal cortex and the hippocampus. It affects an entirely different type of neurotransmitter system than current antidepressants.

People suffering from depression have a lowered number of connections between nerve cells in regions of the brain that regulate mood and thought. Ron Duman, professor of psychology and neurobiology at Yale, was able to produce similar changes in the brains of rats by exposing them to chronic stress. Giving these rats a single dose of ketamine restored the neural deficits caused by the exposure to stress.

The restoration was nearly immediate and clearly visible under the microscope. The conclusion is that ketamine relieves depression by triggering the release of the neurotransmitter glutamate, which in turn stimulates growth of synapses and restores the lost neuronal (synaptic) connections.

There's similar evidence in humans. Carlos Zarate, a researcher at the National Institute of Mental Health, published a study in August that tested the effect of ketamine in 30 patients whose depression had proven resistant to other treatments. Zarate observed that the patients whose symptoms improved when given ketamine showed changes in brainwave activity that were consistent with a strengthening of neuronal connections in areas of the brain involved in depression.

Since 2000, when the first study showing that ketamine could rapidly relieve depression was published, it's been the goal of researchers to produce drugs that work like ketamine but without ketamine's side effects. Understanding the mechanism of how ketamine works is crucial to that effort. And that mechanism appears to be restoring lost connections in the brain.

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Several drugs that seek to mimic ketamine's benefits without its side effects are already being tested in humans, and some have shown encouraging preliminary results. One drug in particular, GLYX-13, has been tested in two large groups of volunteers. Results of these tests are expected to become available in December.

Current antidepressants are ineffective in about one-third of all depression patients and take weeks or months to relieve symptoms when they do work. The last truly new drugs developed to treat depression were the selective serotonin reuptake inhibitors (SSRIs), such as Prozac, developed in the 1980s.

A new class of drugs that work with ketamine's rapidity but without its drawbacks will markedly change the face of depression treatment for the better.

Duman thinks that the discovery of ketamine's ability to rapidly ease symptoms of depression may ultimately turn out to be the most significant discovery in the treatment of depression made in the past 50 years.

A review article by Duman and colleagues that details recent advances in ketamine research was published online in the journal, Science. An article by Zarate and co-workers detailing ketamine's effects on patients with treatment-resistant depression was published online ahead of print by the Journal of Affective Disorders.